Tetrahydroindazoles as Interleukin‑2
Inducible
T‑Cell Kinase Inhibitors. Part II. Second-Generation Analogues
with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation
in Vivo
- Publication date
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Abstract
The medicinal chemistry community
has directed considerable efforts
toward the discovery of selective inhibitors of interleukin-2 inducible
T-cell kinase (ITK), given its role in T-cell signaling downstream
of the T-cell receptor (TCR) and the implications of this target for
inflammatory disorders such as asthma. We have previously disclosed
a structure- and property-guided lead optimization effort which resulted
in the discovery of a new series of tetrahydroindazole-containing
selective ITK inhibitors. Herein we disclose further optimization
of this series that resulted in further potency improvements, reduced
off-target receptor binding liabilities, and reduced cytotoxicity.
Specifically, we have identified a correlation between the basicity
of solubilizing elements in the ITK inhibitors and off-target antiproliferative
effects, which was exploited to reduce cytotoxicity while maintaining
kinase selectivity. Optimized analogues were shown to reduce IL-2
and IL-13 production in vivo following oral or intraperitoneal dosing
in mice